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Metformin Safety In Patients With Chronic Kidney Disease And Its Benefits

Mar 12, 2019
 
Editor: Steve Freed, R.PH., CDE

Author: Dahlia Elimairi, Pharm D Student, UC Denver Skaggs School of Pharmacy

In patients with stage 3 kidney disease, metformin use may be safe and may reduce the risk of mortality and cardiovascular events.

Metformin has not been well studied in patients with impaired kidney function. It was considered unsafe for use in individuals with moderate or severe chronic kidney disease (CKD) due to the potential to induce lactic acidosis, but this was revised recently by the FDA and they have concluded that metformin can be used safely in patients with mild impairment in kidney function and in some patients with moderate impairment in kidney function.

A new study cohort analyzed data from the Trial to Reduce Cardiovascular Events with Aranesp (darbepoeitin-alfa) Therapy (TREAT trial), which enrolled patients with diabetes and chronic kidney disease to darbepoetin alfa or placebo.

The aim of the study was to determine whether metformin has specific cardiovascular or kidney disease benefits in the setting of chronic kidney disease (CKD). They analyzed associations of metformin use with survival, cardiovascular and kidney disease outcomes among 4,038 individuals with diabetes and CKD, including 591 subjects who used metformin among whom 386 had ≥stage G 3b CKD.

All-cause mortality, cardiovascular death, cardiovascular events (death, heart failure hospitalization, myocardial infarction, stroke, or myocardial ischemia), end stage renal disease (ESRD), and the kidney disease composite (ESRD or death) were compared in subjects who used metformin and subjects with diabetes who did not use metformin and CKD enrolled in the TREAT trial. Outcomes were compared after propensity matching users and non-users and in multivariable proportional hazards models.

Compared with use of regimens not including metformin, metformin use was associated

with significantly lower risks of all-cause mortality, cardiovascular mortality, and

a combined cardiovascular disease endpoint that were robust across statistical techniques and that persisted after adjustment for established clinical and demographic risk factors. In contrast, there was no evidence of significant kidney-specific benefits from metformin use and associations with a reduced risk of the combination of death or ESRD were primarily due to effects on overall survival, although confidence intervals for this endpoint were wide despite a large number of ESRD events. Lactic acidosis was rare and non-fatal, and, although not definitive, the results suggest that metformin may lower the risk of death and cardiovascular events that are not ESRD in individuals with stage G 3 CKD.

Although the analysis suggests that metformin may be associated with greater reduction in risk of the combined cardiovascular disease outcome among individuals with CKD stages G 1–3 than CKD stages G 4-5, they did not identify significant differences in efficacy by CKD stage for the other outcomes, and there was no evidence of harm in CKD stages G 4–5.

The study concluded that metformin may be safer for use in CKD than previously considered and may lower the risk of death and cardiovascular events in individuals with stage 3 CKD. The findings suggest that metformin may have significant benefits for individuals with moderate CKD and should not be withheld based on kidney function in those with stage G 3 CKD.

In a previous study by R. Roussel et al. of patients with diabetes and atherosclerosis, metformin was associated with significantly reduced mortality among 4,960 who had stage 3 CKD, but was not associated with mortality among 563 patients who had stage G 4–5 CKD.

These data may be useful to inform decisions to utilize or withhold metformin in the setting of diabetes with late-stage CKD and suggest the need for randomized studies to better assess the appropriate role for metformin in this population.

Larger, randomized trials are warranted to confirm these benefits and to assess whether they extend to later stages of CKD and to provide more precise and generalizable risk estimates. Also studies that compare metformin to the newer agents SGLT-2 inhibitors and glucagon-like peptide 1 agonists in patients with chronic kidney disease are needed.

Practice Pearls:

  • Metformin may be safer for use in CKD than previously considered and may lower the risk of death and cardiovascular events in individuals with stage 3 CKD
  • Mortality benefits was not seen among patients with chronic kidney disease G 4–5
  • Larger randomized trials are needed to further support these findings and compare metformin to the newer agents in patients with chronic kidney disease.

References:

Charytan DM, Solomon SD, Ivanovich P, Remuzzi G, Cooper ME, McGill JB, Parving HH, Parfrey P, Singh AK, Burdmann EA, Levey AS, Eckardt KU, McMurray JJV, Weinrauch LA, Liu J, Claggett B, Lewis EF, Pfeffer MA. Metformin Use and Cardiovascular Events in Patients with Type 2 Diabetes and Chronic Kidney Disease. Diabetes Obes Metab. 2019 Jan 22. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM494140.pdf

Roussel R, Travert F, Pasquet B, Wilson PW, Smith SC Jr, Goto S, Ravaud P,Marre M, Porath A, Bhatt DL, Steg PG; Reduction of Atherothrombosis for Continued Health (REACH) Registry Investigators. Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med. 2010 Nov 22;170(21):1892-9.

Dahlia Elimairi, Pharm D Student, UC Denver Skaggs School of Pharmacy